Into the Deep: New Findings in the Farthest Reaches of the Asthmatic Lung

At an industry-sponsored symposium held in conjunction with CHEST 2003, the annual meeting of the American College of Chest Physicians in Orlando, Florida. three leaders in pulmonary research who discussed recent developments in our understanding of the asthmatic lung and new treatment options available.

The program was chaired by Richard Martin, MD, FCCP, Head of the Pulmonary Division and Vice Chair of the Department of Medicine at National Jewish Medical and Research Center and Professor of Medicine at the University of Colorado Health Sciences Center in Denver, Colorado.

This program was funded by an unrestricted educational grant from Forest Pharmaceuticals, Inc.

Deeper Understanding of the Pathophysiology of Asthma

“ I’m going to change the way you think about asthma, and I’m going to change the way you think about how the lung is changed in asthma, and cause you to refocus your attention not so much on the large airways but on smaller airways perhaps even on the alveolus, because that may, in fact, be where a lot of the problem is,” began Charles Irvin, PhD, Professor in the Departments of Medicine and of Physiology and Biophysics at the University of Vermont College of Medicine, Burlington, Vermont. To illustrate, Dr. Irvin showed the audience a picture of an asthmatic lung and said, “the mucus formed in this airway is incredibly important, simply in terms of status asthmatics and death,” adding, “but to this day, I cannot tell you anything about abnormal smooth muscle function. I am not convinced that smooth muscle is important, I’m not even convinced that it’s important in asthma and whether remodeling is important in asthma. It is still, as far as I’m concerned, an open question.”

More important to asthma and asthma treatment are the small airways and the alveoli. Animal and human studies have shown that the small airways in the lung have a different physiology and pathology in asthma compared to large airways. “We know that they’re different, we know that they’re different in the pathology, but what is the evidence that peripheral lung is even functionally involved in asthma?” asked Dr. Irvin. In humans, bronchoscopic studies have shown airway resistance to be much higher in the small airways of mild asthmatics (Am Rev Respir Dis. 1990;141: 584-588).The small airways are also hyp-erresponsive to a cool dry air challenge in asthmatics (Am J Respir Crit Care Med. 1995;152:1784-1790). In a study in collaboration with Dr. Kraft, Dr. Irvin stated that nocturnal (4 a.m.) peripheral resistance was significantly higher in nocturnal asthmatics than in non-nocturnal asthmatics (Am J Respir Crit Care Med. 2001;163:1551-1556) (Figure 1). Furthermore, nocturnal asthmatics had much more eosinophils in their alveolus compared to their airways. This was not observed in non-nocturnal asthmatics (Am J Respir Crit Care Med. 1996;156: 1505-1510). “At four a.m., the change is most impressive in both groups, though not in terms of airway function, but actually in the alveolus part,” said Dr. Irvin, adding, “if you then correlate this to the fall in FEV1 that occurs overnight in these patients, the correlation is not in the airway tissue, but it appears to be deeper in the alveolus.”

At the University of Virginia, hyperpolarized gas MR imaging has shown there are large holes in the images, even in mild asthmatic patients. This suggests that the small airways are not just narrowed, but closed. Dr. Irvin acknowledged that studies of the small airways are extremely difficult to perform for the simple reason that small airways in asthmatic patients are fairly unstable. Part of the reason may be due to changes in the airway epithelium that may allow increased fibrin and thrombin in the airways.

Measuring Small Airways Dysfunction
“In the study that we did in the nocturnal asthmatics, we looked at lung volumes because it has always been taught that residual volume is, in fact, a very good index of small airways disease, and you can see very tight correlations, particularly at four p.m., between residual volume and peripheral resistance,” said Dr. Irvin, adding, “so by just measuring residual volume in the body box, you’re going to have a pretty good idea what’s going on in the small, distal parts of the lung” (Am J Respir Crit Care Med. 2001;163:1551-1556). Another method to show that small airways are affected by asthma is frequency dependence of resistance (J Appl Physiol. 1979;47:161-168).

Concluding Remarks
Small airways (< 2 mm) in the distal lung are an important part of mild asthma. Distal lung dysfunction is related to hyperresponsiveness and distal lung dysfunction increases with asthma severity. Assessment of distal lung function is possible using residual volume or frequency dependence of resistance measurements. Interestingly, the mucus plug that causes asthmatic attacks also is the plug that may prevent medications from getting to distal regions of the lung. Treatment options that allow medications to get past this plug and into the distal regions of the lung are needed.

Reaching Deeper in the Lung with New Formulations and Delivery Systems

Three strategies used by companies to improve medication delivery [i.e, chlorofluorocarbon (CFC) vs hydrofluoroalkane (HFA)] to small airways in the lung include: 1) change from a suspension CFC pMDI to suspension HFA pMDI; 2) change from a suspension CFC to a suspension HFA (i.e., Aerobid); 3) change from suspension CFC to solution HFA with integral actuator/spacer (i.e., triamcinolone, flunisolide). “So we have these three possibilities and we have a number of products on the market or about to be released for the patient’s use,” said Myrna Dolovich, PEng, Associate Clinical Professor of Medicine and Radiology at McMaster University in Hamilton, Ontario. These products include:

Solution formulations

• Beclomethasone dipropionate
• Flunisolide (+ integral actuator/ spacer)
• Triamcinolone acetonide
• Ciclesonide

Suspension formulations
• Fluticasone/salmeterol
• Mometasone furoate

There are three important characteristics of the HFA formulations that make it superior to CFC suspensions. Firstly, the temperature of the spray is warmer, making it more comfortable for patients, especially children. Secondly, the forward velocity of the spray is reduced further adding to the comfort of the spray. Thirdly, HFC aerosols are smaller in particle size (< 1 µm) compared to CFC aerosols (> 3 µm), allowing more medication to enter further into the lung. The addition of a spacer in some devices decreases the oropharyngeal dose inhaled, which is a further advantage, especially in children where you want to reduce the total body dose as much as possible.

One micrometer aerosols
“What do we know about one micron aerosols?” asked Prof. Dolovich. Generally, they behave like a gas with minimum sedimentation rate and a minimum diffusion rate. As such, most of the aerosol will be exhaled. Patients should be advised to breathe in slowly to try and attain laminar flow of air which will in turn, help promote medication delivery of aerosol to the distal airways. Prof. Dolovich said, “you want your patient to inhale slowly so that the airflow tracks the airway distribution and with reduced turbulence to avoid catching particles at those points of airway narrowing.”

There is evidence that the 1 µm aerosols do reach distal airways. Prof. Dolovich showed a 2D image of an asthmatic subject (FEV1 > 50%) given a labeled 1 µm aerosol. The aerosol reached distal regions of the lung as demonstrated by its rapid absorption from the lung periphery, leaving the more central airways still containing radioactivity. Indirect evidence showing that extra-fine aerosols reach the distal lung is further provided in the study by Hauber et al. showing both central and peripheral airway eosinophils to be reduced in a similar manner following treatment with flunisolide HFA (J Allergy Clin Immunol. 2003;112:56-63) (Figure 1). Prof. Dolovich concluded, “Inflammation is present throughout the airway, both in the central and peripheral airways, and giving these extra-fine aerosols allows us to reduce that inflammation to a more manageable level.”
Is smaller better?

Prof. Dolovich et al. (Am J Respir Crit Care Med .2000;161:A33) compared HFA and CFC delivery systems and found the extra-fine aerosols in the HFA delivery system to significantly deliver more medication. In one patient with asthma, the HFA system delivered 70% of the drug to the lung compared to only 17% using the CFC delivery system. Prof. Dolovich stated this patient was not atypical and this example is supported by radiolabeled studies with flunisolide showing delivery percentages of 68.3% (HFA) versus 19.7% (CFC) (J Aerosol Med .2001;14:197-208).

This data also supports the hypothesis that extra-fine aerosols are reaching the distal airways but Prof. Dolovich cautioned the audience that larger-sized aerosols do reach the lung but larger doses of drug need to be inhaled to match the total administered HFA deposited dose. Two-dimensional imaging studies have shown that the ratio of central to peripheral deposition is similar in both CFC and HFA delivery systems. However, more in-depth analysis using 3-dimensional imaging techniques have shown HFA delivery systems to significantly increase the amount of peripheral airways receiving the medication, compared to CFC (Figure 2) (Newman SP et al. 60th Anniversary Meeting of the American Academy of Allergy Asthma & Immunology; March 7–12, 2003; Denver, CO). “By using tomographic 3-D imaging, they were able to indicate that there is more aerosol in the peripheral lung, and this would correlate with the findings of eosinophils in the periphery and their reduction in numbers and thus level of inflammation with treatment,” said Prof. Dolovich, adding “that imaging can help sort out some of these deposition issues, but you have to have the correct imaging technique.”

Concluding Remarks
“We have shown that HFA solution aerosols produce finer particles, a one micron aerosol compared to the traditional CFC aerosols that are now being phased out or have been phased out,” concluded Prof. Dolovich adding, “these extra-fine aerosols show greater deposition in the lung with the total dose of corticosteroid to the lung increased three- to four-fold.”

Recent Advances in the Management of Asthma New Approach to Comparing Medications

Monica Kraft, MD, FCCP, Associate Professor in the Department of Medicine at the National Jewish Medical and Research Center and at the University of Colorado Health Sciences Center in Denver, CO, concluded the symposium with an overview of recent advances in asthma treatment. Dr. Kraft pointed out that steroids are generally the first-line treatment for asthmatics and the choice of which inhaled steroid to use is oftentimes based on convenience, micrograms per puff, taste preference, and/or cost. There are many inhalers available and it is difficult for practitioners to determine which is best for each patient. At the asthma clinical research network, Dr. Kraft and others performed studies [DICE (dose of inhaled corticosteroid equi-systemic) and MICE (measurement of inhaled corticosteroid efficacy)] to establish a methodology to compare equivalent doses of each inhaled steroid. Among the data collected was the observation that measurement of cortisol levels is only a good predictor of efficacy at low to medium doses of the steroids for the simple reason that FEV1 changes peak at these lower doses (J Allergy Clin Immunol. 2002;109:410-418). Dr. Kraft said, “a plateau occurred with this medication, suggesting that more wasn’t necessarily better, that if one was going to respond to an inhaled steroid, then in fact, it would happen relatively early on with regard to the FEV1.”

Dr. Kraft and others have also become interested in the high variability of efficacy in patients. For example, post-hoc analysis of the MICE study (J Allergy Clin Immunol .2002;109:410-418) revealed that approximately one-third of patients were good responders, one-third were partial responders and one-third were poor responders. Dr. Kraft said studies are currently underway to determine if we can predict which patients will be good responders. For example, Dr. Kraft’s group has observed that if a patient had a significant bronchodilator response to albuterol (> 15%), with a high-exhaled nitric oxide, and increased sputum eosinophils (> 2-3%), then that patient would tend to be a steroid responder. “So we’re taking these predictors now, and putting them into a new study a priori to see if they will hold up and really allow us to determine if a patient is going to be a steroid responder,” said Dr. Kraft.

Treating Inflammation in the Distal Lung
“We’re here today to talk about the distal lung, so I would like to perhaps hypothesize that distal lung inflammation may be one of the reasons for this variability in steroid response,” stated Dr. Kraft. In an examination of alveolar tissue inflammation, “we saw a lot more alveolar tissue eosinophils in the nocturnal asthmatics compared to the non-nocturnal asthmatics, and many more alveolar tissue eosinophils at night as compared to day,” stated Dr. Kraft, adding, “we didn’t see a whole lot in the larger airways.”

In addition, the overnight increase in small airway tissue eosinophils is correlated with thoracic gas volume and inversely correlated with a drop in FEV1 (Am J Resp Crit Care Med. 1996;154: 1505-1516). Such studies further illustrate the importance of both the distal airways and inflammation has on asthma and Dr. Kraft hopes that we can use lung volumes as a noninvasive method to predict distal lung inflammation since it is much easier than bronchoscopy or transbronchial biopsy.

Fortunately, the new HFA formulations appear to reach these distal regions and can attenuate the inflammation. Studies with flunisolide have shown it can reduce inflammation in both peripheral and central airways (J Allergy Clin Immunol. 2003; 112;58-62) (Figure 1, previous page).

Non-Corticosteroid Therapy
Anti-IL5 was tested as an asthmatic medication but results were disappointing (Lancet. 2000;356:2144-2149). A follow-up study found that the poor results were probably due to the fact that much of the injected medication stayed in the periphery where there was 88% suppression of eosinophils. In the bronchial mucosa, there was only a 55% suppression of eosinophils (Am J Respir Crit Care Med. 2003;167:199-204). Studies with IL-12 were also developed and although it reduced eosinophils, there was no change in lung function (Lancet. 2000;356:2148-2153).

Another treatment option may be omalizumab, which is a monoclonal antibody against IgE. Two studies involving moderate asthmatic patients given omalizumab (+ an inhaled steroid) measured exacerbations and found the addition of omalizumab reduced exacerbations significantly but had no effect on FEV1 (J Allergy Clin Immunol. 2001; 108:184-190; Eur Respir J. 2001;18: 254-261). Dr. Kraft added, “I’ve done a study with this compound looking at inflammation in the tissues, and omalizumab actually does decrease eosinophils and T-cells, so there actually is a significant anti-inflammatory effect going on.”

Concluding Remarks
“Hopefully I’ve gotten you thinking that there is significant variability in the response to corticosteroids and that, in fact, a potential reason for that could be distal lung inflammation,” concluded Dr. Kraft. At present, corticosteroids remain the first-line treatment for asthma patients but anti-IgE medications (omalizumab) may be useful in some patients but further studies are needed.